Abstract 2250: Combination of PARP inhibitor, Olaparib with pathway-targeted drug, vandetanib (Caprelsa™) in TNBC: A proof of principle study to determine the role of PI3K-AKT-mTOR or RAS-MAPK pathways in targeted drug-response

Abstract

Introduction: Identification of the driving genetic alteration(s) (e.g. BRCA, PTEN) and deregulated signaling pathway(s) are critical for the successful discovery of molecular targets in Triple Negative Breast Cancer (TNBC). Understanding of the biology of TN tumor cells has resulted in the recognition of a few molecular targets for the development of novel therapeutics including, (1) cell surface receptor tyrosine kinase(s) (RTKs, e.g. EGFR), (2) signaling pathway(s) (PI3K-mTOR, RAS-MAPK), and (3) DNA-damage (chemo- or radiotherapy) repair pathway. We hypothesize that the genetic background (expression of RTKs, BRCA mutations, absence of PTEN or activating mutations of PIK3CA / RAF) influences the response of TNBC cells to a combination treatment of drugs. Methods: We tested the effects of combination of EGFR/VEGFR inhibitor (vandetanib) with PARPi (Olaparib) in presence of DNA-damaging agent (carboplatin) on, (a) cell survival/proliferation and their, signaling marker(s), (b) integrin-directed migration, (c) fibronectin-directed matrigel-invasion, (d) adhesion-dependent survival, (e) vascular mimicry (VM), and (f) clonogenic survival in TNBC cell lines with high expression of EGFR (MDA-MB468, SUM149), BRCA mutations (HCC1937, SUM149), no expression of PTEN protein (HCC70, HCC1937, MDA-MB468, SUM149), PIK3CA mutation (BT20), and RAS/RAF mutation (MDA-MB231). Results: Data showed that, (1) although EC50s ranged from 5-15 µM for vandetanib in cells, the PTEN-null cells exhibited comparatively favorable EC50s, (2) vandetanib (10 µM) inhibited phosphorylation of AKT (S473 & T308), S6RP, 4EBP1 and ERK by 1 hour, (3) MDA-MB468 cell line was the most sensitive to vandetanib (∼ 0.05 µM) when combined with 10 µM fixed dose of Olaparib, and (4) a combination of vandetanib with Olaparib plus carboplatin time dependently increased caspase-3 and PARP cleavage, inhibited VM (6, 24 h), blocked fibronectin-directed migration, and suppressed clonogenic growth to a greater extent in PTEN-null cells lines. Conclusion: Anti-proliferative/pro-apoptotic, and anti-migratory/invasive effects of vandetanib (alone or in combination with carboplatin plus Olaparib) were most prominent in PTEN-null and high EGFR-expressing cells. However, given that the inhibitory activity of olaparib occurred at relatively high concentrations we are currently pursuing studies to refine the dose response relationship. In addition we are examining (1) the mechanistic relationship between the anti-proliferative/pro-apoptotic effects and the effectors status of EGFR/ PI3K pathway following treatment with vandetanib (in combination with PARPi plus temozolomide), and (2) effect of vandetanib on the hypoxic-response of tumor and endothelial cells, the results of which will be presented in the meeting.

Abstract 2250: Combination of PARP inhibitor, Olaparib with pathway-targeted drug, vandetanib (Caprelsa™) in TNBC: A proof of principle study to determine the role of PI3K-AKT-mTOR or RAS-MAPK pathways in targeted drug-response

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Abstract 2250: Combination of PARP inhibitor, Olaparib with pathway-targeted drug, vandetanib (Caprelsa™) in TNBC: A proof of principle study to determine the role of PI3K-AKT-mTOR or RAS-MAPK pathways in targeted drug-response